FAP therapy nucresiran safely reduces TTR in healthy people: Trial
Blood TTR levels 70% lower after one year of single dosing
A single dose of nucresiran, an experimental therapy for familial amyloid polyneuropathy (FAP) and other forms of ATTR amyloidosis, safely resulted in significant and sustained reductions in blood levels of the disease-driving transthyretin (TTR) protein in healthy people.
That’s according to interim results from an ongoing, placebo-controlled Phase 1 clinical trial (NCT05661916) presented at the American Heart Association Scientific Sessions 2024, held Nov. 8-10 in Chicago.
“We are very excited by these new Phase 1 data with nucresiran, our next-generation TTR-targeting RNAi therapeutic, which demonstrated that a single dose of [300 mg or higher] achieved rapid knockdown of TTR greater than 90% from Day 15 that was sustained to at least six months,” Pushkal Garg, MD, chief medical officer of Alnylam Pharmaceuticals, the therapy’s developer, said in a company press release.
Blood TTR levels were 70% lower one year after the single dosing, showing that the therapy has the “potential to achieve durability supportive of biannual or annual dosing, representing a potential new paradigm in the treatment of ATTR amyloidosis,” Garg said. “We look forward to sharing Phase 3 development plans in the first quarter of 2025.”
ATTR amyloidosis refers to a group of diseases marked by the formation of toxic clumps, or amyloid fibrils, made of the TTR protein that accumulate in the body’s tissues and organs, causing damage. FAP is a type of inherited ATTR amyloidosis caused by mutations in the TTR gene, which provides cells with instructions for making the TTR protein. In people with FAP, toxic TTR clumps accumulate mainly in nerves outside the brain and spinal cord, leading to a range of nerve damage-related symptoms.
RNA interference
Nucresiran, formerly known as ALN-TTRsc04, uses a process known as RNA interference, or RNAi, to suppress the production of both healthy and mutated TTR protein.
In RNAi, small RNA molecules bind to messenger RNA, the intermediate molecule derived from DNA that is used as a template for protein production, marking it for destruction. By reducing levels of mutated TTR protein, nucresiran is expected to help slow disease progression in people with FAP and other forms of ATTR amyloidosis.
The next-generation therapy, administered via a subcutaneous (under-the-skin) injection, was designed with Alnylam’s proprietary IKARIA platform, which aims to develop longer-lasting RNAi-based therapies that are very target-specific and have the potential for annual dosing.
The Phase 1 trial is evaluating the safety, tolerability, pharmacodynamics, and pharmacokinetics of single ascending doses of nucresiran in up to 180 healthy adults, ages 18-65. Pharmacodynamics refers to the therapy’s effects on the body, and pharmacokinetics to its movement into, through, and out of the body.
The preliminary results pertained to 48 healthy adults who were randomly assigned to receive a single subcutaneous injection of either nucresiran (at a dose of 5, 25, 100, 300, 600, or 900 mg) or a placebo.
Those given a single 300 mg dose experienced a 90.3% reduction in blood TTR levels 15 days after treatment. The peak level reduction was observed 29 days after treatment, when TTR was lowered by 96.5%. About six months after treatment, levels were still reduced by 92.6%, and at one year, levels showed a 71.12% reduction.
A single, 600 mg dose of nucresiran reduced TTR levels by 95% after 15 days, by 97.8% after about a month, and by 96% after six months. The highest tested dose, 900 mg, decreased blood TTR levels by 91.7% after 15 days, by 96.7% after one month, and by 94.2% after six months. One-year data were not yet available for participants given 600 mg or 900 mg of nucresiran.
Results varied little among participants. TTR reductions about a month after treatment with 300 mg of nucresiran ranged from 96%-96.7%. “We are encouraged by the potential of nucresiran to reduce interpatient variability in TTR lowering,” Garg said.
The therapy was generally well tolerated at all tested doses. Most adverse events were mild in severity, and none was considered related to nucresiran. There were no reports of injection-site reactions or safety concerns, including liver-related events. The treatment “has been well tolerated at all dose levels tested to date,” Garg said.
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